FDA Approves Revlimid (lenalidomide) for the Treatment of Patients with Relapsed or Refractory Mantle Cell Lymphoma

Lenalidomide  (Revlimid)

EP 0925294; US 5635517; WO 9803502,Drugs Fut 2003, 28, 5, 425.Bioorg Med Chem Lett 1999, 9, 11, 1625

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Jun. 5, 2013– Celgene Corporation today announced the U.S. Food and Drug Administration (FDA) has approved the company’s supplemental new drug application (sNDA) for Revlimid (lenalidomide) for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

Revlimid is used to treat a certain type of myelodysplastic syndrome (a group of conditions in which the bone marrow produces blood cells that are misshapen and does not produce enough healthy blood cells) caused by an abnormal chromosome. Revlimid is also used to treat anemia (a lack of red blood cells in the body) and along with dexamethasone for the treatment of multiple myeloma (a type of cancer of the bone marrow) who have received at least one prior therapy.

Lenalidomide  (Revlimid) is a derivative of thalidomide introduced in 2004.

It was initially intended as a treatment for multiple myeloma, for which thalidomide is an accepted therapeutic treatment. Lenalidomide has also shown efficacy in the class of hematological disorders known as myelodysplastic syndromes (MDS). Lenalidomide has significantly improved overall survival in myeloma (which generally carries a poor prognosis), although toxicity remains an issue for users.  It costs $163,381 per year for the average patient.

Use in USA -

On June 29, 2006, lenalidomide received U.S. Food and Drug Administration(FDA) clearance for use in combination with dexamethasone in patients with multiple myeloma who have received at least one prior therapy.

As of 2011, the FDA has initiated an ongoing review of Revlimid. The review focuses on clinical trials which found that Revlimid caused an increased risk of developing new malignancies such as acute myelogenous leukemia (AML) and B-cell lymphoma.The FDA is currently advising all patients on Revlimid to continue their treatment

Use in the UK -

On 23 April 2009, The National Institute for Health and Clinical Excellence(NICE) issued a Final Appraisal Determination (FAD) approving lenalidomide, in combination with dexamethasone, as an option to treat patients who suffer from multiple myeloma who have received two or more prior therapies in England and Wales.

Use in Australia -

While lenalidomide is not approved for first-line treatment of multiple myeloma in Australia, in clinical trials of newly diagnosed multiple myeloma, a four-fold increase in the incidence of second primary malignancies has been observed in patients receiving lenalidomide (7.0%) compared to controls (1.8%). These included cases of acute myeloid leukaemia, myelodysplastic syndrome and solid tumours in patients receiving lenalidomide.

Green chemistry has ecological, financial benefits for Pfizer

When people hear the word "green" these days, they automatically think "environmentally friendly." But among chemists at Pfizer Inc. in Groton, the word also denotes efficiency, which equals a different type of "green" - money.

And Pfizer's local laboratories have been saving the company plenty of money - millions of dollars, most likely, though the company won't provide specific figures - over the past few years through a relatively new idea called green chemistry. Scientists in Groton are constantly reviewing and revising the chemical processes that go into the manufacture of top-selling medicines such as the cholesterol blockbuster Lipitor and pain reliever Lyrica, making sure new drugs are produced in the most efficient manner possible.

"Pfizer is a leader in both the research and implementation of green-chemistry and green-engineering practices," said S. Stewart Slater, a professor of chemical engineering at Rowan University in Glassboro, N.J.

By going green - which local scientists spearheaded at Pfizer a decade ago, though the chemistry principles date to the early 1990s - the making of pharmaceuticals is being done in a less wasteful, safer and more benign manner.

"By being green chemists, I think we provide a particular benefit to the environment," said John Wong, senior research fellow at Pfizer's Groton labs and leader of the eight-member Green Chemistry Team there. "When you use enzymes to do chemistry, they are not toxic and certainly environmentally friendly."

In the pharmaceutical industry, green chemistry often means the replacement of organic solvents with enzymes, commonly referred to as "nature's catalysts" and naturally occurring in all living organisms. Companies try to implement green chemistry ideas right from the start, because changing drug formulations after a product is out requires additional human testing for safety and effectiveness.

Eric Watters, environmental manager of the Groton facility and a team member, said the use of green-chemistry methods doesn't have a big impact on the local air and water because the pharmaceutical giant no longer has extensive manufacturing facilities here. It's at the company's drug-making plants worldwide that the use of green chemistry is most noticeable on the environment, he said.

The environmental impact is felt most profoundly with reductions in the amount of carbon dioxide released into the atmosphere. Efficiencies and cost savings come largely from reduced use of raw materials and significant cuts in energy use.

To give an example, Wong pointed to a new process for manufacturing Lyrica developed by his team in Groton that reduced carbon-dioxide emissions by 43 percent using one of Pfizer's measurement tools. The company expects a further reduction in emissions of 20 percent as it continues to refine the method through the end of next year, he said.

Avoiding chemical waste

"The pharmaceutical sector has embraced green chemistry most enthusiastically, perhaps because it has the most to gain," according to an article last month in Nature News. "Pharmaceutical plants typically generate 25 to 100 kilograms of waste per kilogram of product, a ratio known as the environmental factor, or 'E-factor.' So there is plenty of room to increase efficiency - and cut costs."

The company expects that green-chemistry processes used to reimagine the production of Lyrica will, over a 13-year period, avoid about 200,000 metric tons of organic chemical waste. Pfizer scientist Peter Dunn, who in 2006 became the pharmaceutical industry's first full-time green chemistry leader, has said the rejiggering of three product lines alone saved the company the cost of 500,000 metric tons of chemicals.

According to Pfizer spokeswoman Sperry Mylott, the company's drugs currently in late-stage development use 24 percent less solvent per kilogram than the most advanced compounds it was testing a few years ago, "thus achieving one of Groton's chemical R&D team's environmental goals two years ahead of schedule."

Chemists do small-scale experiments in Groton before trying out their ideas on a bigger stage with Pfizer's manufacturing partners, said local team leader Wong. The idea is to be as "atom economical" as possible, he added, meaning that less material used up front leads to less waste in the end.

"The company is quite good at implementing process improvements," he said.

Although the pharmaceutical industry in general did not embrace the principles of green chemistry right away - chemical companies faced with outcries after the Love Canal fiasco and the Bhopal disaster had a greater incentive - it now is more motivated, as drug discovery has waned and cost-cutting is getting more attention.

As far back as 1998, Pfizer scientists in Sandwich, England, had worked to improve efficiencies in the manufacture of Viagra, which at that point produced 105 kilograms of waste for every kilogram of product. Pfizer eventually reduced the E-factor to 8, meaning the production of Viagra became more than 90 percent more efficient.

"Ultimately, it's all economics that drives it," said Connecticut College chemistry chair Marc Zimmer. "You can't just let waste go down the drain anymore. You have to dispose of it, and that means you have to pay for it."

Improving production methods of antidepressant Zoloft as well as Viagra and Lyrica have won Pfizer major green chemistry awards. The 2002 Zoloft green chemistry project, conducted at the Groton labs, won the U.S. Environmental Protection Agency's Presidential Green Chemistry Award.

Early stage development

The local labs also have their own internal awards, and winners may designate the prize to an educational institution. In the past year, the prize went to Pfizer scientist Jamison Tuttle, who designated that the $5,000 award be given to his former Connecticut College professor Timo Ovaska, who in turn plans to use it for research stipends for summer students.

"Green chemistry is still in an early stage," Ovaska said, "but it's definitely having more and more of an impact."

Wong said Pfizer doesn't force green chemistry on anyone, but there is a constant effort to educate employees in the science. He added that chemists have been quick to embrace the concept and are always brainstorming and experimenting with new ideas for making pharmaceutical production less costly and easier on the environment.

"It's part of our day-to-day activities," he said.

Ordinary Measures : Everything I needed to know I learned in Freshman Chemistry 101

For Years, pharma has been the villain in most public opinion polls. But now, the tide seems to be turning. Last month brought buzz about the film, Extraordinary Measures. You’ve no doubt heard all about the inspiring story of John Crowley, a pharmaceutical exec who quit his job to fund research into cures for Pompe disease. Not only did he save the lives of his own, and many other, children, he opened up the field of orphan drugs.

Although critics are lukewarm, they say the movie does reveal to the public more of the complexity and challenge of drug development and manufacturing. What could be better than that? But lately I’ve been wondering about the “other” side of manufacturing—the side that could never make it to Hollywood: cGMPs and quality control. Drug recalls in the U.S. have been trending upwards. In the U.K., according to a recent study by Blueview Group, drug and medical device recalls increased 400% between 2004 and 2008, due mainly to manufacturing defects, packaging or labeling issues, or compromised sterility. 

Pharmaceutical quality control reached a climax in the news last summer, after FDA issued Genzyme a 483 for cGMP problems at its Allston Landing plant. This plant manufactures the orphan drugs Cerezyme and Fabrazyme, worth nearly $2 billion in sales each year. A dissident shareholder, Relational Investors, sued the company, its principal alleging that Genzyme overpaid for acquisitions and underinvested in manufacturing. The problems cost Genzyme dearly, as FDA did not approve its improved Pompe disease treatment (which is now being re-evaluated) and reportedly streamlined the approval process for a competitor’s product. Last month, Genzyme hired a new QC chief, and contracted with Hospira to handle filling. Relational withdrew its suit, and hopes to settle its diff erences with the company.

But the question still lingers. Is the industry, in its desperate attempt to acquire innovation and reinvent itself, underinvesting in core quality control operations? Last month saw another major pharma company, J&J, dogged by quality control issues. Th e company has led the industry in Lean Six Sigma and operational excellence initiatives, so this news may have surprised some. But J&J had to recall more lots of Tylenol and other over-thecounter medications, which were tainted with a chemical used to treat wooden pallets. FDA alleged that J&J was aware of the problem a full year before it took action.

It’s easy to point the finger at senior management. But is that the whole story? Is everyone on your team being rigorous about quality? We often lament about pharma’s silos and its “data rich, information poor” problem. But that doesn’t mean that each and every critical data point shouldn’t be recorded, transferred and shared. Last month, we interviewed experts on the topic of tech transfer, and found that people oft en fail to transfer basic information to internal partners, or external CMOs. Information is missing, isn’t recorded, and, in deals involving China and Japan, isn’t translated. And analytical methods and SOPs are the areas where people most often trip up. This has an obvious impact on CAPA and fundamental quality control.

Contributing editor and NIR expert Emil Ciurczak suggests that some have “gotten lazy and stupid” about documenting critical details. “Everything you need to know to pass an FDA inspection you learned in freshman chemistry class,” he says. One industry consultant recalls a consent decree in the 1980s, where a lab technician openly admitted to FDA to taking notes down in pencil, then changing them to ink later on. She also responded to questions about an SOP. “Nobody does it that way,” she said. “Everyone knows it won’t work that way.”

“How could anyone have hired such an incompetent tech?” you ask. But is it really that farfetched? Read any 483’s lately? It’s the ordinary measures, as well as the extraordinary ones, that count.

Pale People May Need Vitamin D Supplements

Researchers at the University of Leeds, funded by Cancer Research UK, suggest that people with very pale skin may be unable to spend enough time in the sun to make the amount of vitamin D the body needs - while also avoiding sunburn. The study, published in Cancer Causes and Control*, suggested that melanoma patients may need vitamin D supplements as well. But researchers also noted that sunlight and supplements are not the only factors that can determine the level of vitamin D in a person's body. Some inherited differences in the way people's bodies process vitamin D into the active form also have a strong effect on people's vitamin D levels.

The study defined the optimal amount of vitamin D required by the body as at least 60nmol/L. However at present there is no universally agreed standard definition of an optimal level of vitamin D.

Professor Julia Newton-Bishop, lead author of the study based in the Cancer Research UK Centre at the University of Leeds, said: "Fair-skinned individuals who burn easily are not able to make enough vitamin D from sunlight and so may need to take vitamin D supplements.

"This should be considered for fair-skinned people living in a mild climate like the UK and melanoma patients in particular."

Researchers took the vitamin D levels of around 1,200 people and found that around 730 people had a sub-optimal level. Those with fair-skin had significantly lower levels. Researchers chose 60nmol/L as the optimal vitamin D level in part because there is evidence that levels lower than this may be linked to greater risk of heart disease and poorer survival from breast cancer.

A consensus between health charities including Cancer Research UK says that levels below 25nmol/L are vitamin D deficient which means that these levels are associated with poor bone health. But some researchers consider that higher levels, around 60nmol/l, may be desirable for optimal health effects.

Sara Hiom, director of health information at Cancer Research UK, said: "We must be careful about raising the definition of deficiency or sufficiency to higher levels until we have more results from trials showing that maintaining such levels has clear health benefits and no health risks.

"If you are worried about your vitamin D levels, our advice is to go see your doctor."

Researchers Discover Genes Involved in Colorectal Cancer

A jumping gene with the fairy tale name "Sleeping Beauty" has helped to unlock vital clues for researchers investigating the genetics of colorectal cancer. A study used the Sleeping Beauty transposon system to profile the repertoire of genes that can drive colorectal cancer, identifying many more than previously thought. Around one third of these genes are mutated in human cancer, which provides strong evidence that they are driver mutations in human tumours.

The collaborative project funded by Cancer Research UK and the Wellcome Trust was led by Dr David Adams from the Wellcome Trust Sanger Institute, and Dr Douglas Winton, of the Cancer Research-UK Cambridge Research Institute.

"These findings, when combined with mutation data from human colon cancers, will drive forward our understanding of the processes that lead to colorectal cancer," says Dr Adams, senior author from the Sanger Institute. "They demonstrate how many genes can contribute to this cancer and how these genes work together in the development of this disease".

The Sleeping Beauty transposon system induces genetic mutations at random, identifying and tagging candidate cancer genes, the drivers that cause colorectal cancer. This system has become critical in uncovering the genetic pathways that cause cancer, and, in this study, the team identify more than 200 genes that can be disrupted in human colorectal cancers.

Colorectal (bowel) cancer is the third most common cancer in the UK, and the second most common cause of cancer deaths after lung cancer; just under 40,000 people were diagnosed with bowel cancer in the UK in 2008 – around 110 people every day - a figure which has shown little improvement over the last decade.

"Our research provides a rich source of candidate genes that represent potential diagnostic, prognostic and therapeutic targets, and defines the breadth of genes that can contribute to cancer of the intestine," says Dr Winton, senior author from the Cancer Research UK Cambridge Research Institute. "It is becoming increasingly clear that cancers are driven by mutations in disparate collections of genes and it is essential that we tease apart the important changes."

Current thinking is that perhaps around 50 major drivers are mutated in any one cancer cell, but the number and identity of all of the cancer drivers, and how many drivers are found in each type of cancer, is largely unknown. By performing screens for cancer genes in the mouse and by then comparing them to data from human tumours the team identified a rich catalogue of new candidate genes helping to refine the genes that genetic pathways that drive bowel cancer development.

"At its heart, cancer is a disease driven by faulty genes," says Dr Lesley Walker, director of cancer information at Cancer Research UK. "Research suggests that each cancer cell has a number of 'driver' faults that make them grow out of control, as well as 'passenger' faults that they pick up as the disease develops. This technique is helping us to tease out the key drivers of bowel cancer, laying the foundations for more effective, targeted treatments for the disease in the future."

The research complements studies by The Cancer Genome Atlas and the International Cancer Genome Consortium, which are cataloguing the mutations responsible for cancer development using next generation DNA sequencing.

Using Viagra to Combat Malignant Melanoma

At first it sounds like good news: The body's own immune system gets active in almost every cancer - however, not necessarily for the benefit of the patient. "We distinguish between two different types of immune response," says Professor Dr. Viktor Umansky, immunologist at DKFZ and University Medical Center Mannheim. "On the one hand, cells of the immune system specifically attack tumor cells. On the other, however, almost every tumor causes in its microenvironment a chronic inflammatory immune response which suppresses the specific antitumor immunity."

In an inflammatory immune response, immune cells of a certain type migrate into the tumor environment and release characteristic immune mediators. "Our aim is to reduce the chronic inflammations and, thus, to support the immune system in actively fighting the cancer," Umansky said.

He and his team have now studied chronic inflammation as it is caused by malignant melanoma. For their research, they used genetically-modified (transgenic) mice that spontaneously develop a type of skin cancer which is very similar to human melanoma. In the tumor environment and in metastatic lymph nodes of the animals, the investigators detected inflammatory mediators such interleukin-1-β and interferon-γ. These immune mediators attract what are called myeloid-derived suppressor cells (MDSC). These immune cells are known to inhibit the immune system's most important tumor-specific fighters, the T cells.

What exactly happens when T cells get under the influence of MDSC? When the researchers exposed T cells obtained from the spleen of a healthy mouse to MDSC in the culture dish, the T cells stopped proliferating. Moreover, the T cells reduced the level of an important activating molecule. "This shows that tumor-specific T cells are actively suppressed by myeloid-derived suppressor cells," said Umansky, explaining their findings.

The melanoma mice were then given sildenafil. This substance, which is better known under its trade name, Viagra®, had already been reported to improve tumor immunity in experimental animal models several times before. Of the mice that had been given the substance with their drinking water, more than twice as many were still alive after about seven weeks as of their untreated fellows. In the animals that had been treated, both the number of tumor-specific T cells and the level of activating molecules had returned to normal. This means that sildenafil successfully neutralizes the chronic inflammation in the melanoma environment and combats the immunosuppressive activity of MDSC.

"Our research approach is special because the disease takes a very similar course in mice as melanoma does in humans," Viktor Umansky said explaining the medical relevance of his findings. "Therefore, it is very well possible that sildenafil can also inhibit the immunosuppressive effects of inflammation and thus improve antitumor immunity in people with melanoma. In this way, the drug may contribute to achieving better treatment results in malignant melanoma."